catalysts Review N-Heterocyclic Carbene Catalysis under Oxidizing Conditions Krzysztof Dzieszkowski and Zbigniew Rafi ´nski* Faculty of Chemistry, Nicolaus Copernicus University in Toru´n,Gagarin Street 7, 87-100 Toru´n,Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-56-611-4530 Received: 17 October 2018; Accepted: 14 November 2018; Published: 16 November 2018 Abstract: N-heterocyclic carbene organocatalysis under oxidizing conditions provides a vast range of various synthetic procedures via diverse mechanisms. The available catalysts, bases, oxidants, and oxidizing methods afford numerous opportunities for developing this branch of organocatalysis. Furthermore, implementation of tandem reactions and cooperative catalysis in the described methodology significantly expands the possibilities of modern organic chemistry. This approach allows the synthesis of different structurally complex and often enantiomerically enriched substances, which can be interesting in terms of biological activity and natural product synthesis. Many esters, amides, thioesters, lactams, lactones, and other cyclic compounds obtained in oxidative or oxygenative reactions promoted by N-heterocyclic carbenes can be interesting precursors in advanced organic synthesis. Sophistication and broad applicability prove that the described synthetic approaches are exceptionally worthy of further development. Keywords: N-heterocyclic carbenes; oxidations; Breslow intermediate; acylazolium; catalysis 1. Introduction N-heterocyclic carbene (NHCs) catalysis is constantly developing as a diverse strategy for the synthesis of complex organic molecules. NHC-catalyzed reactions enable the formation of many carbon-carbon and carbon-heteroatom bonds, including heterocyclic rings [1–8]. N-heterocyclic carbenes were originally applied in umpolung benzoin condensation [9], which is still the most examined NHC-catalyzed reaction model [10]. In this type of reaction, a Breslow intermediate is generated after the nucleophilic attack of carbene on a carbonyl carbon atom. Moreover, this intermediate exhibits nucleophilic properties, in contrast to carbonyl compounds which are typically electrophilic agents (Figure1)[11]. Unique α,β-unsaturated acylazoliums can also be generated by the reaction of NHCs with α,β-unsaturated enol esters or ethers [12–14], acyl fluorides [15,16], ynals [17–20], or 2-bromoenals [21–24]. In contrast to the nucleophilic Breslow intermediate, the aforementioned acylazoliums exhibit electrophilic properties. Furthermore, the Breslow intermediate can be oxidized to acylazolium, which is a very useful acylium cation synthon. Consequently, among other protocols, oxidative NHC catalysis is a unique method for the synthesis of amides and esters [25–29]. This review contains examples of a broad range of oxygenative or oxidative NHC-catalyzed reactions, which are crucial for modern organic synthesis. The article is focused on the application of NHC catalysis under oxidizing conditions, as an example of cooperative catalysis with the use of an external oxidant [30]. The aim of this work is also the nomenclature overview of this significant and relevant synthetic approach, and a breakdown by oxidation path. Moreover, this review is aimed at updating the status of NHC-catalyzed reactions under oxidizing conditions in existing review papers [31,32]. Catalysts 2018, 8, 549; doi:10.3390/catal8110549 www.mdpi.com/journal/catalysts Catalysts 2018, 8, x FOR PEER REVIEW 2 of 15 Catalysts 2018, 8, 549 2 of 16 Catalysts 2018, 8, x FOR PEER REVIEW 2 of 15 Figure 1. Benzoin condensation mechanism. Figure 1. Benzoin condensation mechanism. 2. Mechanistic and Nomenclature Issues 2. Mechanistic and Nomenclature Issues 2. MechanisticOxidative NHCand Nomenclature catalysis, similarly Issues to the classical umpolung process, is initiated by the Breslow umpolung intermediate,Oxidative which NHC is catalysis, generated similarly from a toN -heterocyclic the classical umpolungcarbene and process, carbonyl is initiated compound—typically by the Breslow N intermediate,aldehyde.intermediate, An whichacylazolium isis generatedgenerated ion, which fromfrom is aa electrophilicN-heterocyclic-heterocyclic acylium carbenecarbene cation andand carbonylcarbonylsynthon, compound—typicallycompound—typicallyis formed via transfer aldehyde.of two electrons AnAn acylazoliumacylazolium from the ion,ion, mentioned whichwhich is is electrophilic intermediateelectrophilic acylium acyliumto the cationoxidant cation synthon, synthon, in theis reaction is formed formed viamixture. via transfer transfer The of twonucleophileof two electrons electrons added from from theas mentioneda thereactant mentioned undergoes intermediate intermediate nucleoph to the oxidant toilic thesubstitution inoxidant the reaction into thethe mixture. reactioncarbonyl The mixture.group nucleophile of Thethe addedacylazoliumnucleophile as a reactant addedion, with undergoesas subsequenta reactant nucleophilic undergoes elimination substitution nucleoph of the azoliumilic to substitution the cation carbonyl and to group regeneration the ofcarbonyl the acylazolium of group the catalyst of ion,the with(Figureacylazolium subsequent 2) [31]. ion, eliminationwith subsequent of the elimination azolium cation of the and azolium regeneration cation ofand the regeneration catalyst (Figure of the2)[ catalyst31]. (Figure 2) [31]. Figure 2. Mechanism of oxidative NHC-catalyzed esterification.esterification. Figure 2. Mechanism of oxidative NHC-catalyzed esterification. On the other other hand, hand, the the Breslow Breslow intermediate intermediate can can be be oxidized oxidized via via oxygen oxygen atom atom transfer transfer from from an an oxidizing agent. After formation of a peroxide zwitterion, a second molecule of aldehyde is oxidizingOn the agent. other After hand, formation the Breslow of a intermediateperoxide zwitterion, can be oxidized a second via molecule oxygen of atom aldehyde transfer is oxidized from an oxidized by the peroxide species, then the azolium intermediate is eliminated and the carboxylate ion byoxidizing the peroxide agent. Afterspecies, formation then the of aazolium peroxide intermediate zwitterion, ais second eliminated molecule and ofthe aldehyde carboxylate is oxidized ion is is formed. Next, the obtained carboxylate participate in the reaction with an electrophile is added to formed.by the peroxide Next, the species,obtained then carboxylate the azolium participate intermediate in the reaction is eliminated with an andelectrophile the carboxylate is added ionto the is the reaction mixture. This path is called oxygenative NHC catalysis, in contrast to the oxidative path reactionformed. Next,mixture. the obtainedThis path carboxylate is called oxygenative participate inNHC the reactioncatalysis, with in contrast an electrophile to the oxidativeis added to path the (Figure3). In oxygenative carboxylations, molecular oxygen can be used as external oxidant. In the (Figurereaction 3). mixture. In oxygenative This path carboxylations, is called oxygenative molecular NHC oxygen catalysis, can be in used contrast as external to the oxidant.oxidative In path the (Figure 3). In oxygenative carboxylations, molecular oxygen can be used as external oxidant. In the Catalysts 2018, 8, 549 3 of 16 Catalysts 2018, 8, x FOR PEER REVIEW 3 of 15 casecase of of spin-allowed spin-allowed oxygenation oxygenation with with O O22, ,the the reaction reaction occurs occurs via via the the single-electron-transfer single-electron-transfer (SET) (SET) processprocess [33]. [33]. Some Some mechanisms mechanisms assume assume that that intermediate intermediate dioxetane dioxetane species species can can be be involved involved [34]. [34]. FigureFigure 3. 3. DifferenceDifference between between oxidative oxidative and and oxygenative oxygenative NHC NHC catalysis catalysis using using oxygen oxygen as as an an oxidant. oxidant. Moreover,Moreover, the the oxygenative oxygenative path path is is not not the the only only po possiblessible reaction reaction mechanism mechanism in in the the case case of of using using molecularmolecular oxygenoxygen as as an oxidant.an oxidant. An acylazoliumAn acylazolium ion can beion formed can be after formed elimination after of elimination a hydroperoxyl of aanion hydroperoxyl from the peroxide anion from zwitterion. the peroxide This path zwitterion. is also oxidative This path NHC is catalysis,also oxidative because NHC an acylazolium catalysis, becauseintermediate an acylazolium is generated intermediate [33]. is generated [33]. 3.3. Oxygenative Oxygenative NHC NHC Catalysis Catalysis OxygenativeOxygenative NHC NHC catalysis catalysis was was first first reported reported by by Deng’s Deng’s group group in in 2010 2010 (Figure (Figure 44a)a) [[35].35]. Benzyl Benzyl benzoatebenzoate derivatives derivatives were were obtained obtained with with good good yiel yieldsds in in the the reaction reaction of of benzaldehydes benzaldehydes with with benzyl benzyl bromidesbromides under under aerobic aerobic conditions, conditions, using using a thiazolium a thiazolium catalyst. catalyst. Similar Similar syntheses syntheses were were described described one yearone yearlater laterby Liu by Liuet al. et al.[36]. [36 They]. They involved involved reactions reactions between between cinnamaldehydes cinnamaldehydes and and cinnamyl cinnamyl bromidesbromides or or allyl allyl bromides bromides using using a a benzimidazolium benzimidazolium catalyst catalyst (Figure (Figure 44b).b).